キーワード：リピッド、糖尿病、動脈硬化、生活習慣病、転写因子

　生物の長い歴史の中で、現代社会はまれに見る飽食と運動不足の時代です。日本人の栄養バランスはエネルギー過多に傾いており、糖尿病・高脂血症・肥満などの生活習慣病が大きな問題となっています。この生活習慣病について、体内に蓄積した脂質の量と質という新たな視点で、分子レベルから個体レベルまで総合的な研究を行っているのが、リサーチユニット「脂質エネルギー代謝」です（図１）。

脂質代謝について分子レベルから個体レベルまでトータルで理解する

私たちは、どんな疾患でもその病態を解明して治療法を開発するためには、分子レベルから個体レベルまでの総合的な研究が必要だと考えています。そして生活習慣病においては、脂質代謝遺伝子の発現バランス異常と、体内での脂質の蓄積が病態解明のキーになると考えています。この考え方に基づき、私たちは最先端技術を駆使して動物実験と細胞レベルの実験を組み合わせた３つの研究プロジェクトに取り組んでいます。
1.　身体がエネルギーの過不足を検知するメカニズムを遺伝子レベルで解明する（図２）
2.　過食や飢餓時に作動する転写因子を解析し脂質代謝の調節メカニズムを解明する（図２）
3.　臓器に蓄積された脂質の質の違いが病態に与える影響を明らかにし、新しい生活習慣病治療法を提案する（図３）

体内の脂質の質：脂肪酸バランスは生活習慣病発症の新しいキーファクター

生活習慣病というと、過食や肥満が原因と考えられています。もちろん過食は避け肥満は解消すべきですが、本当に有効な生活習慣病の予防や治療のためには、 身体に溜まった脂質の量だけを考えていては不十分なようです。私たちは体内に蓄積している脂質の質（脂肪酸バランス）を制御する酵素（Elovl6）を発見し研究を展開しています。肥満糖尿病モデルマウスを使って行った研究では、この酵素を遺伝子改変して体内の脂肪酸バランスを変化させると、臓器にたまっている脂質の量は同程度でもインスリンが効きやすく、血糖が改善し糖尿病・動脈硬化・脂肪肝を妨ぐことが明らかになりました（図３左）。このことは、肥満の改善を必要としない、新たな生活習慣病治療法の可能性を示しています。
さらに興味深いことに、体内の脂肪酸バランスは脳や肺などにおいても重要で、行動や呼吸の働きにも影響を与えていることが分かってきました（図３右）。私たちはエネルギー代謝の量的制御と脂質の質的制御の研究を両輪に、様々な生命現象や疾患の病態との繫がりを解明し、新たな治療戦略を考えていきます。

 (取材：平成25年10月10日)

Key words: lipids, diabetes, arteriosclerosis, lifestyle-related diseases, transcription factors

Modern society suffers from an epidemic of overeating and underactivity, a rare phenomenon in the long history of human and land creature. Along with a recent trend toward a positive nutrient intake balance, i.e., excessive energy intake, metabolic or lifestyle-related diseases such as diabetes, hyperlipidemia, and obesity, have become a major health issue among human being. From a new perspective, focusing on the quantity and quality of lipids accumulated in the body, the research unit “Lipid and Energy Metabolism” conducts comprehensive studies regarding lifestyle-related diseases from the molecular to whole-organism level (Figure 1).

Figure 1 : Perspectives for the elucidation of disturbances in energy metabolism and lifestyle-related diseases with a focus on lipid metabolism

Toward a comprehensive understanding of lipid metabolism from the molecular to whole-organism level

It is necessary to conduct comprehensive studies across a range of scales from the molecular to whole-organism level to elucidate the pathology of a disease and develop effective treatment strategies against it. We suggest that the unbalanced expression of genes regulating lipid metabolism as well as the accumulation of lipids in the body may be key to understanding the pathology of metabolic disorders. Based on this, and using the most advanced technologies available, we are working on three research projects that integrate animal studies and cell-based experiments aiming to:
1. Characterize, at the gene level, the mechanisms by which the body recognizes a lack or excess of energy (Figure 2)

Figure 2 : Schematic diagrams of Projects 1 and 2

2. Analyze transcription factors that function during energy excess and depletion (satiation and starvation), and elucidate the regulatory mechanisms of lipid metabolism in the whole body, organs and cells (Figure 2)
3. Clarify the effects of differences in the quality of lipids (especially fatty acid composition) accumulated in different organs on the pathologies of different lifestyle-related diseases to provide a new and comprehensive treatment strategy against these problems (Figure 3).

Figure 3 : A new treatment strategy focusing on the quality of lipids involving Elovl6 (Project 3)

Quality of tissue lipids: The fatty acid composition is a novel key factor in the development of lifestyle-related diseases

Obesity-related or lifestyle-related diseases are thought to be caused by obesity. Although appropriate adjustment of energy balance and resolution of obesity still remains an important recommendation, but hard to continue, approaches focusing only on the quantity of lipids accumulated in the body would be insufficient to develop effective strategies for the prevention and treatment of lifestyle-related diseases. Switching the focus to quality of lipids, we have conducted extensive studies on Elovl6, an enzyme that modulates the quality (fatty acid composition) of lipids stored in the body, since we identified it. In a study using an obese diabetic mouse model, alterations in the tissue fatty acid composition by genetic modification of this enzyme resulted in increased insulin sensitivity and decreased blood glucose levels, despite there being no marked changes in the amount of lipids in organs, leading to protection against diabetes, arteriosclerosis, and hepatic steatosis (Figure 3, left). This suggests the potential for a novel therapeutic approach to lifestyle-related diseases targeting Elovl6 in which the management of obesity is not necessary.
Furthermore, it is interesting that the tissue fatty acid composition has been shown to play important roles in the brain and lung to influence behavior and respiratory activity, respectively (Figure 3, right). Through research on both quantitative aspects of the regulation of energy metabolism and qualitative aspects of the regulation of tissue lipids, we are continuing our efforts to elucidate the involvement of such regulatory mechanisms in biological phenomena and disease pathologies to develop new treatment strategies against lifestyle-related diseases.